Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

Abstract

Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.

Proteotoxic Stress and Cell Death in Cancer Cells

“…Cancer cells convive with proteotoxic stress by upregulating all the possible mechanisms that are able to maintain proteostasis [ 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 ]. As a consequence, cancer cells are more dependent on the presence of HSPs from UPS for their growth and survival [ 205 , 206 ].…”

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

“…Due to the interconnectivity of the proteostasis network, manipulating expression levels of one chaperone can have unforeseen effects. On the one hand, inhibition of a central chaperone can lead to compensatory upregulation of other chaperones within the network (Sannino et al, 2018 ). On the other hand, high concentrations of certain chaperones can also have an inhibitory effect.…”

Proteotoxic Stress and Cell Death in Cancer Cells

“…Cancer cells convive with proteotoxic stress by up-regulating all the possible mechanisms able to maintain proteostasis. [196][197][198][199][200][201][202][203][204]. As a consequence, cancer cells are more dependent on the presence of HSP and from the UPS for their growth and survival [205,206].…”